Transplanted into rat, organ was able to produce urine

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Researchers from Massachusetts General Hospital announced Sunday an important advance in the effort to build replacement organs: a bioengineered rat kidney that, when transplanted into a rat, was capable of producing urine.

Years of research remain before scientists even contemplate testing such a transplant in a person, but the team plans to take a step toward that goal in the next month, transplanting bioengineered pig kidneys into live animals to see if they will function.

“If you put the organs side by side, it would be hard to tell which is the bioengineered organ and which is the real organ,” said Dr. Joren Madsen, director of the Mass. General Transplant Center, who plans to collaborate with the team on the pig trials. “However, there are a couple problems that need to be solved before we can bring these to the clinic. The function of the organs . . . is modest at best.”

The researchers used a shortcut to engineer the kidneys, starting with a scaffold of collagen, which is what remained after living cells were washed away from another rat’s kidney. They then seeded this matrix with a cocktail of cells, including kidney cells from newborn rats, which grew into a functioning organ.

The hope is that the technique could address two problems facing people waiting for a transplant: rejection of the donor organ by the recipient’s immune system, and the shortage of organs. Although many challenges remain, scientists anticipate the technology could be used to create organs from a patient’s cells by using stem cell technology to seed the donor organ once it is stripped. If a way to mass produce the structural organ scaffold is developed, the technique could also help meet the need for donor organs. One possible source could be a pig’s kidney, stripped of its cells and repopulated with human cells.

Madsen said there was tremendous excitement about the approach being developed by Dr. Harald C. Ott, a surgeon and researcher at the Mass. General Center for Regenerative Medicine who led the new work published online in the journal Nature Medicine. That is because the need is great. Although about 18,000 kidney transplants are done in the United States each year, about 100,000 people are on the waiting list for one. Roughly 400,000 more are on dialysis and could benefit from made-to-order organs.

Five years ago, Ott described the technique, in a paper with the alluring subtitle, "using nature’s platform to engineer a bioartificial heart.” As a research fellow at the University of Minnesota, he had discovered that flushing a rat’s heart with a detergent, such as one found in shampoo, could remove the living cells from the organ and leave behind a collagen matrix. This solved one of the major problems of building organs from scratch. Instead of trying to mimic all the complexities of an organ, he could preserve the intricate structure nature had built. Then, he seeded it with heart cells taken from newborn rats, which were able to home in on the correct places to grow.

In the years since, he has refined the technique and extended it to other organs, including lungs, the pancreas, and the kidney. In the new work, he also showed that the rat kidney had rudimentary function. One test of kidney function is its ability to clear a substance called creatinine from the blood, and Ott said the bioengineered kidney had around 5 percent of the function of a normal kidney. That is far from ready for prime time, but the kidney may be low-hanging fruit for bioengineers trying to build replacement parts. Unlike other organs, for example, it is not mechanically active — it is a filtration system that sits still. Perhaps more important, it also would not have to be 100 percent functional to be useful.

“I don’t think our place in this organ-regeneration effort is to figure it all out, but to show it’s a valid platform to get everyone on board — stem cell scientists, transplant surgeons,” Ott said. “My hope is that with this proof of principle, people become aware . . . and start working on this problem.”
He is focused on refining the technique and understanding how to improve the function of the kidney and other organs.

Dr. Laura Niklason, a professor of anesthesia and biomedical engineering at Yale University, has used a similar approach to wash away cells from lung tissue and reseed it with new ones. Although the experiments are exciting, she said there are some obstacles that will take years to surmount.

Challenges range from biomedical engineering problems to complex issues of stem cell biology. For example, it is difficult to get full coverage of the denuded organ with the new cells. And scientists have yet to refine the recipe for reseeding kidneys. Niklason said there are also questions about whether the process used to wash away the original cells may damage the scaffolding underneath.

“What’s been done here with the kidney has been sort of contemplated and predicted for a year or two, so I think it’s great,” Niklason said. But it is important that people, especially patients who may be hopeful this technology could help them, are aware of how far there is to go, she added.

“I think the road is longer than people may think,” Niklason said. “When embryonic stem cells were first discovered or developed, people were talking then [that] we were going to have organs in just a couple of years. There was a lot of exuberance then, and there’s a lot of exuberance around this technology now.”

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